Asymmetric syntheses of 3,4-syn- and 3,4-anti-3-substituted-4-aminopiperidin-2-ones: application to the asymmetric synthesis of (+)-(3S,4R)-cisapride

作者：Davies Stephen G^*; Huckvale Rosemary; Lee James A; Lorkin Thomas J A; Roberts Paul M; Thomson James E

来源：Tetrahedron, 2012, 68(15): 3263-3275.

DOI：10.1016/j.tet.2011.12.084

• Lithium amide
• Conjugate addition
• 4-Aminopiperidin-2-one
• 4-Aminopiperidine
• (+)-(3S,4R)-Cisapride

The conjugate addition of lithium (R)-N-benzyl-N-(alpha-methylbenzyl)amide to delta-(N-allylamino)-alpha,beta-unsaturated esters, followed by N-deallylation and cyclisation of the resultant beta,delta-diamino esters, gives the corresponding 4-aminopiperidin-2-ones as single diastereoisomers (>99:1 dr). Subsequent deprotonation with LiHMDS and functionalisation of the resultant lithium enolate gives 3,4-anti-3-substituted-4-aminopiperidin-2-ones in >99:1 dr. Alternatively, in situ oxidation of the intermediate lithium (Z)-beta-amino enolates formed upon conjugate addition gives alpha-hydroxy-beta,delta-diamino esters, which after N-deallylation and cyclisation gives the corresponding 3,4-syn-3-hydroxy-4-aminopiperidin-2-ones in >99:1 dr. The utility of this methodology was successfully demonstrated in a concise asymmetric synthesis of the gastroprokinetic agent (+)-(35,4R)-cisapride {(+)-(35,4R)-N(1)-[3'-(4 ''-fluorophenoxy)propyl]- 3-methoxy-4-(2'''-methoxy-4'''-amino-5'''-chlorobenzamido)piperidine} in nine steps from commercially available starting materials with an overall yield of 19%.

• 出版日期2012-4-15